Clusterin (CLU) is a secreted multi-function glycoprotein that has been associated with clearance of debris, apoptosis inhibition, tissue remodeling, complement inhibition, regulation of complement-mediated cell lysis, membrane recycling, cell-cell adhesion and epithelial growth. CLU is a single 9-exon gene expressing three protein forms1,2,3. Each of the forms has distinct sub-cellular localizations and biological functions4,5; CLU has nearly ubiquitous tissue distribution. Due to functions such as regulatory activity on complement, CLU is involved in inflammation and autoimmunity.
CLU is implicated in a number of disease states including cancer, Alzheimer's disease, and rheumatoid arthritis6,7,8. It is overexpressed in several human cancers, and its suppression deems cancer cells sensitive to chemotherapeutic drug-mediated apoptosis9. However, despite the many reports on CLU functionality and its relation to tumorigenesis, many contradictions in the data still exist. Understanding the role of CLU in tumorigenesis is complicated not only by the existence of different protein forms but also by the changes of tumors over time and the treatment-induced alterations such as hormone ablation or chemotherapy10,11,12. CLU has been found to be dysregulated in many types of cancer including prostate and breast cancer13,14,15. Similarly, CLU was initially shown to be upregulated in Alzheimer's Disease (AD) and later observed to bind to amyloid beta peptides and preclude defibrilization of the amyloid peptides. Amongst its numerous functions in the brain, CLU aids in the clearance of amyloid-beta peptides and fibrils by binding to megalin receptors to enhance their endocytosis within glial cells7. Further, CLU is also present in lipoprotein particles and hence regulates cholesterol and lipid metabolism, which is compromised in the brains of AD patients7.
Chronic allograft nephropathy (CAN) (chronic allograft injury/rejection) is of great concern in long term renal allograft survival. CAN differs from ‘chronic rejection’ in that it is an end point of tubular atrophy and interstitial fibrosis (IF/TA) in the graft caused by a series of immune and non-immune insults to the kidney, leading ultimately to graft failure.
Interstitial fibrosis is considered to be present when the supporting connective tissue in the renal parenchyma exceeds 5% of the cortical area.
Tubular atrophy refers to the presence of tubules with thick redundant basement membranes, or a reduction of greater than 50% in tubular diameter compared to surrounding non-atrophic tubules. IF/TA is contributed to by pre-existing donor factors such as donor age, underlying disease or donor-recipient size disparity; by immune factors involving acute and chronic humoral and cellular processes; or by post-transplant factors including drug toxicity and infection. A number of immune mechanisms contribute to CAN including acute and chronic alloantibody-mediated rejection as well as acute and chronic cellular rejection. The consequences of antibody mediated processes are a distinct set of histological features, mainly Transplant Glomerulopathy (TG), which is characterized by a doubling of the glomerular basement membrane (GBM), which is usually accompanied by IF/TA. Recurrent late acute cellular or antibody mediated rejection which is resistant to treatment is a critical predictor of CAN development.
What is needed in the art are markers whose expression can be used to identify patients suffering from kidney diseases and predict the development of kidney fibrosis. In addition, such markers are needed to identify renal allograft recipients who are at risk for developing IF/TA and represent targets for therapeutic intervention to prevent the development of IF/TA at an early stage, thereby preventing the development of CAN.